There are various kinds of anticancer agents such as an alkylating agent, a platinum agent, an antimetabolite, an antitumor antibiotic, and an antitumor plant alkaloid. In addition, those anticancer agents exhibit the effects in some cases and exhibit no effect in other cases, which depends on the kind of cancer. However, it is known that, even if the cancer is a kind in which an anticancer agent is confirmed to be effective, the anticancer agent exhibits the effect in some cases and exhibits no effect in other cases, leading to interindividual differences. Whether an anticancer agent exhibits the effect on the cancer of an individual patient or not is designated to as sensitivity to the anticancer agent.
Oxaliplatin, i.e. (SP-4-2)-[(1R,2R)-cyclohexane-1, 2-diamine-κN,κN′][ethanedioato (2-)-κO1,κO2]platinum (IUPAC), is a third-generation platinum-based complex anticancer agent. The action mechanism thereof is thought to be, like cisplatin (CDDP) and carboplatin (CBCDA) that are preceding drugs, based on DNA synthesis inhibition and/or protein synthesis inhibition by formation of a cross-link with a DNA base. The oxaliplatin (L-OHP) exhibits an antitumor effect on colorectal cancer, in which CDDP and CBCDA are ineffective, and shows different spectrum of antitumor activity from that of a conventional platinum-based complex anticancer agent. In America, oxaliplatin for use in combination with fluorouracil (5-FU) and levofolinate (LV) was approved as a first line therapy for metastatic colorectal cancer in January 2004. In Japan, in April 2005, the oxaliplatin was listed on National Health Insurance (NHI) price listing in the case of combination use thereof with an infusional fluorouracil and levofolinate (FOLFOX4 regimen) for advanced/recurrent colorectal cancer not amenable to curative surgical resection. In the treatment for advanced/recurrent colorectal cancer, while the survival with a 5-FU/LV regimen which had been given until the early 1990s was in the range of 10 to 12 months, the survival with the FOLFOX regimen combined with oxaliplatin reaches about twice the period (19.5 months). In addition, in a study with stage II/III cases, there is reported the efficacy of the FOLFOX regimen when compared with the 5-FU/LV regimen in a postoperative adjuvant chemotherapy.
Accordingly, though the oxaliplatin has not yet been approved, oxaliplatin is expected to be supplemental approval for use of patient treatment with colorectal cancer in postoperative adjuvant chemotherapy and to be effective in the patients.
Nevertheless, an objective response rate of the FOLFOX regimen against advanced/recurrent colorectal cancer is about 50%. In other words, it is suggested that the half of the patients who have received the FOLFOX regimen do not achieve the effect. In addition, the use of the oxaliplatin causes a peripheral neuropathy at high frequency in addition to neutropenia, which is not a fatal adverse event but is a factor causing a difficulty in continuing the therapy. Therefore, if a patient who is expected to achieve the response (responder) and a patient who is not expected to achieve the response (non-responder) can be predicted or diagnosed before starting the therapy, highly effective and safe chemotherapy can be realized. Further, in general, the treatment schedule of cancer chemotherapy extends for a long period. Therefore, monitoring sensitivity to an anticancer agent chronologically during the therapy enables the determination on whether the therapy must be continued or not, leads to reduction in burden of the patient and adverse events, and may also be effective from the viewpoint of the medical economy. The establishment of a biomarker for predicting a therapeutic response is urged for “personalized medicine” in which the therapeutic response of individual patients is predicted and an appropriate therapy is selected.
As factors related with the therapeutic response to the oxaliplatin, the following may be mainly involved:
(1) enhancement of the ability of excision repairing damaged DNA by the oxaliplatin;
(2) inactivation (detoxication) of the oxaliplatin (activated form) in cells; and
(3) reduction in accumulation amount of the oxaliplatin in cells.
There are conducted clinical studies on the therapeutic response in a therapy using oxaliplatin and 5-FU in combination for colorectal cancer patients, and clinical studies related with the above items (1) to (3) as predictive factors for prognosis.
Regarding the item (1), there is reported that excision repair cross-complementing group 1 (ERCC1) gene expression amount in tumor is a prognostic factor, the ERCC1 playing an important role in a nucleotide excision repair (NER) (Non-patent Document 1). There is reported that a patient having C/C homozygote of C118T, which is one of single nucleotide polymorphisms (SNPs) of ERCC1, shows more favorable survival rate than that of a patient having at least one or more T alleles (Non-patent Document 2). The genetic polymorphism which causes an amino acid mutation of Lys751Gln in Xeroderma pigmentosum D (XPD, also known as ERCC2), is reported to be involved in tumor reduction rate or the survival (Non-patent Documents 2 and 3). In the base excision repair (BER), there is reported the relationship between the tumor reduction effect and the genetic polymorphism which causes the amino acid mutation of Arg399Gln in X-ray repair cross-complementing group 1 (XRCC1) and, the XRCC1 encoding the protein which may be involved in the effective repair of the breakage of a DNA single strand formed by exposure to an alkylating agent or the like (Non-patent Document 4). However, by the analysis targeting the same patients afterwards, the genetic polymorphism is reported not to influence clinical prognosis (Non-patent Document 2). The DNA mismatch repair (MMR) may also be related with the reduction in sensitivity to cisplatin. However, in a study in vitro, MMR is reported not to be involved in the repair of DNA damaged by oxaliplatin (Non-patent Document 5).
Regarding the item (2), glutathione-S-transferase (GST) is one of enzymes which are responsible for the second phase reaction of the detoxication and metabolism, and inactivates a drug by catalyzing the formation of a conjugation of a platinum-DNA adduct and glutathione. Among GST subtypes, GSTP1 has a high expression level in colorectal cancer. In addition, the genetic polymorphism of the GSTP1, which causes the amino acid mutation of Ile105Val, is reported to be related with the survival (median survival: Ile/Ile, 7.9 months; Ile/Val, 13.3 months; and Val/Val, 24.9 months) (Non-patent Document 6).
Regarding the item (3), in a study using cultured cells, it is reported organic cation transporters (OCTs) are related with the transport of oxaliplatin into the cells and the sensitivity (Non-patent Document 7). In addition, there is reported a relationship between a transporter involving the transport of a copper or a heavy metal, such as ATP7A or ATP7B, and the sensitivity (Non-patent Documents 8 and 9). However, there is no clinical study on the relationship between the expression of those transporters and the therapeutic response to oxaliplatin.
In recent clinical study for advanced colorectal cancer received FOLFOX regimen, it is reported that the genetic polymorphism of ERCC1 (Asn118Asn) and the genetic polymorphism of XPD (Lys751Gln) are independently related with the progression-free survival (PFS). However, there is not found the relationship between the genetic polymorphism of GSTP1 (Ile105Val) and PFS, and it is recognized that the genetic polymorphism tends to have a relationship with oxaliplatin-induced neurotoxicity (Non-patent Document 10).
In studies in vitro, there are many reports on a resistance-related factor of the cisplatin which is a platinum-based complex, preceding drug. There is also reported the relationship between oxaliplatin and apoptosis-related factors such as FAS/FASL and Bcl-xL (Non-patent Documents 11 and 12). However, depending on the kind of cancer, the oxaliplatin exhibits different therapeutic response from the cisplatin. In addition, the cellular response of a cancer cell to a platinum DNA adduct responsible for a cytotoxic activity of oxaliplatin is hardly clarified. A biomarker capable of clearly predicting a therapeutic response to a chemotherapy using the oxaliplatin has been yet to be established.